Restenosis remains a major limiting factor in the percutaneous treatment of coronary artery disease. Despite improvements in restenosis rates achieved from the use of stents and the introduction of drug-eluting stents, restenosis persists in a small percentage of patients. The sequence of events contributing to restenosis is initiated at the stent site as a result of arterial wall trauma, endothelial injury and the release of growth factors, chemoattractants, and inflammatory mediators. These events induce platelet and leukocyte activation and trigger the coagulation cascade. Although the underlying pathophysiology is not uniformly accepted, major pathological findings in acute or chronic stent failure include the deposition of fibrin and platelets, suggesting that a key event in development of restenosis is thrombus formation.
Treatment with stents reduces restenosis compared to balloon angioplasty and now drug-eluting stents have further reduced restenosis rates. However, it is well recognized that most patients treated with bare metal stents develop clinically irrelevant degrees of intimal proliferation and therefore would not necessarily have benefited from the implantation of a drug-eluting stent. See R. Moreno, et al., Drug-eluting stent thrombosis: results from a pooled analysis including 10 randomized studies; J Am Coll Cardiol. 2005; 45: 9549. Nevertheless, the current practice is to implant the more costly drug-eluting stents in the majority of patients undergoing percutaneous intervention. See H. C. Lowe, et al., Coronary in-stent restenosis: current status and future strategies; J Am Coll Cardiol. 2002; 39: 183-93. The ability to predict which patients are most prone to developing neointimal formation could lead to more selective use of drug-eluting stents and tailor the intensity of antiproliferative therapy.
Platelet-related periprocedural thrombotic and inflammatory processes that influence neointimal hyperplasia and angiogenesis are considered important risk factors for restenosis. See B. Chandrasekar et al., Platelets and restenosis; J Am Coll Cardiol. 2000; 35: 555-62. In addition, preexisting inflammatory mediators and hypercoagulable factors have also been proposed to influence the process. Despite an established mechanism linking thrombogenesis to the restenosis process, there are few data in humans that have examined the relation of ex vivo measurements of platelet reactivity to restenosis. This information might be clinically useful in evaluating patients undergoing Percutaneous Cardiovascular Intervention (PCI) to identify a subgroup who may benefit from more aggressive therapy aimed at disrupting the sequence of events leading to restenosis. The ability to predict which patients are most prone to developing neointimal formation could also lead to more selective use of the more costly drug-eluting stents (DES). Use of DES has reduced restenosis rates. Currently, DES are routinely implanted in the majority of patients undergoing PCI without consideration as to whether the clinically irrelevant degrees of intimal proliferation that develop in most patients treated with bare metal stents warrant this practice. Moreover, there is concern that DES have a greater risk of thrombosis than bare metal stents.
At this time, there is no uniformly accepted method to determine which patients are at greatest risk for developing stent restenosis. A major cost savings would result from a method that reliably predicted those patients at greatest risk. These patients would be treated with the more costly drug-eluting strategy whereas those at minimal risk would receive the less expensive bare metal stent. It is well known that specific angiographic and clinical features are associated with a higher risk of restenosis. These include the presence of diabetes, small vessels, long lesions and bifurcation disease. In addition, a strategy that determines who will benefit from DES will entail much less use of dual antiplatelet therapy that is required indefinitely in patients treated with DES due to the excess hazard of stent thrombosis.
Presently, there are no laboratory tests that predict the occurrence of restenosis. Platelets play a fundamental role in the genesis of stent restenosis by modulating coagulation, inflammation, and smooth muscle proliferation. Thrombi with high tensile strength may facilitate neointimal hyperplasia at the stent site. Platelet-related periprocedural thrombotic and inflammatory processes that influence neointimal hyperplasia and angiogenesis are considered important risk factors for restenosis in animal models. See P. A. Gurbel, et al., Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING Study; J Am Coll Cardiol. 2005; 46: 1820-26. Despite these established mechanisms, there are few data in humans that examined the relation of ex vivo measurements of platelet reactivity to restenosis. Moreover, preexisting inflammatory and hypercoaguable factors have also been proposed as important factors influencing restenosis. Moreover, patients with rapid thrombin generation would be expected to readily form thrombi.
There is a need in the field for a method to accurately risk-stratify patients for restenosis. This methodology would therefore tailor patient therapy during stent implantation. This method would assist in the decision making for using a bare metal stent versus a drug-eluting stent and, moreover, would also determine the intensity of drug delivery based on the individual patient's risk.